The impairment of glucose tolerance with normal ageing is well recognized but its mechanisms and differentiation from non-insulin dependent diabetes mellitus (NIDDM) remain unclear. Further understanding is essential, however, for the formulation of a rational approach to the glucose intolerance of ageing. Although both ageing and NIDDM are characterized by peripheral insulin resistance, the contribution of the liver to glucose intolerance in these conditions is uncertain. The aim of this study, therefore, is the study of hepatic glucose metabolism before and after glucose ingestion in normal ageing and NIDDM y the combined application of isotope dilution and the forearm techniques. Hepatic glucose output (HGO) has been studied in ageing and NIDDM but the results are conflicting. Changes in hepatic glucose utilization (HGU) have not been studied but two characteristics make HGU amenable to noninvasive investigation namely (a) the reversible phosphorylation of glucose through a futile cycle to glucose-6-phosphate, the rapid, reversible isomerisation of which to fructose-6-phosphate results in the detritiation of 2-3H-glucose but not 6-3H-glucose and (b) the conversion of glucose to glycogen through an indirect pathway involving its initial breakdown to lactate, a proportion of which is released into the plasma. Impaired HGU due to increased futile cycling (FC) in NIDDM during intravenous glucose infusions using 2-3H-glucose and 3-3H-glucose has been reported but data after oral glucose loading in NIDDM and any comparable studies in the elderly are lacking. Defective irreversible hepatic glucose uptake after glucose ingestion can thus be determined firstly as the difference in glucose disappearance (Rd) using 2-3H- glucose and 6-3H-glucose during their simultaneous primed-constant infusion before and after glucose ingestion (75 g). Secondly, hepatic metabolism of glucose to 3-carbon units can be assessed by studying the increase in lactate turnover after glucose ingestion, using the primed- constant infusion of U-14 C-lactate. HGO, defective HGU due to increased FC, and lactate turnover will be compared in normal young and elderly men, males with NIDDM and age-matched normal men, each group comprising about eight volunteers. The data, the first of their kind, will further clarify the importance, differences and similarities of the hepatic response to glucose ingestion in normal ageing and NIDDM.